October 31, 2003

Study finds way to dramatically increase hematopoietic stem cells

Researchers from the MGH Center for Regenerative Medicine and Technology (CRMT) and the Endocrine Unit have found a way to significantly increase production of hematopoietic stem cells in a mouse model. Expanding numbers of these cells, which can develop into any kind of blood cell, could greatly increase how many patients could receive stem cell transplants for certain cancers. The study in the Oct. 23 issue of Nature also identifies a treatment strategy that might duplicate this effect in patients, and the researchers are preparing clinical trials for that approach.

"The ability to enhance the number of stem cells an individual produces could have an immediate impact on patient care," says David Scadden, MD, (above) director of CRMT, the paper's senior author. Clinical use of hematopoietic stem cells has always been difficult because they naturally occur in very small numbers and rarely reproduce. Although most research groups seeking ways to expand stem cell populations have tried adding growth factors to bone marrow samples, the MGH researchers focused on the natural environment where stem cells develop, which in adults is the marrow cavity inside long bones.

The fact that stem cells are usually found in the outer layer of marrow, adjacent to the inner layer of bone, suggested that osteoblasts — cells that generate new bone tissue to replace old bone and are found in that inner bone region — might have an impact on stem cells. To investigate that possibility, the researchers first studied a group of transgenic mice with an overly active version of a protein that turns on osteoblasts. They found that the mice had increased levels of both osteoblasts in their bones and stem cells in their bone marrow, although other marrow cell levels were normal. Because the protein that turns on osteoblasts is a receptor for the bone-building parathyroid hormone (PTH), the researchers investigated whether injections of PTH — an FDA-approved treatment for osteoporosis developed through MGH research — might produce the same stem cell effect seen in the transgenic mice.

After several preliminary experiments with encouraging results, the research team carried out a bone marrow transplant protocol, including marrow destruction and the transfer of only a few stem cells, in mice that had previously received PTH injections and in a control group. Although only 27 percent of the control mice survived for 28 days after transplantation, all of the PTH-treated mice survived, and examination of their marrow confirmed that the donor tissue had proliferated. "This work opens a new angle from which we can attack the challenges of stem cell transplantation, focusing on the environment to achieve a stem cell effect," says Scadden.

Co-first authors of the paper are Laura Calvi, MD, who is now at the University of Rochester Medical School, and Gregor Adams, PhD, of CRMT, Partners AIDS Research Center and the MGH Cancer Center. Other MGH co-authors include Katherine Weibrecht, Douglas Olson, Roderick Martin, Melissa Knight, Ernestina Schipani, MD, PhD, Paola Divieti, Richard Bringhurst, MD, and Henry Kronenberg, MD.